Hepatocellular Carcinoma (HCC) is the third leading cause of cancer deaths in the world with a median survival time of only 7.8 months in untreated patients. Conditionally replicating viruses targeted to tumors are being developed as a novel class of oncolytic agents for cancer treatment. Vesicular Stomatitis Virus (VSV) is a cytoplasmic RNA virus with inherent specificity for replication in tumor cells due to their attenuated anti- viral responses. We demonstrated robust VSV replication and cytopathic effects in cultured rat and human HCC cells, while normal rat and human hepatocytes were refractory. We have constructed a fusogenic rVSV vector and showed that through hepatic artery infusion, it reached and replicated in large multi-focal HCC lesions in the livers of syngeneic and immune-competent rats that led to massive tumor destruction and survival prolongation, and without liver pathology. While encouraging, intratumoral virus replication peaked after only one day and long-term survival was achieved in only a minor fraction of the treated animals. The logarithmic decline in intratumoral virus titers beyond one-day was co-incidental with the infiltration and accumulation of NK cells, neutrophils and macrophages at the tumor sites, and oncolysis was substantially enhanced by antibody-mediated depletion of these inflammatory cells prior to virus treatment. We hypothesize that the oncolytic potency VSV can be significantly elevated by vector-mediated expression of genes from heterologous viruses that suppress NK cell activity and chemotaxis of inflammatory cells, so that intratumoral virus replication will be extended from one to several days needed by the host to mount a neutralizing antibody response, which will lead to robust oncolysis and substantially prolonged survival. Additionally, at virus dosages above the maximum tolerated dose some treated rats exhibited signs of neuro-pathology manifested by limb paralysis, and virus was detected in neurons in the brain and spinal cord. We hypothesize that neuronal virus replication and spread can be inhibited by molecularly engineering the VSV genome so that the translation of pertinent viral mRNAs will be under the direction of internal ribosome entry sites of heterologous viruses that are non-functional in neurons but active in HCC cells. The successful conduct of the proposed research may lead to the future development of potent and neuro-attenuated rVSV vectors as effective and safe oncolytic agents to treat patients with advanced HCC and other cancers.